A Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane in Pancreatic Cancer

Recent strategies have focused on improving the efficacy of gemcitabine either by improving the method of delivery, or by combining gemcitabine with other non-cross resistant agents. A sequence of Phase III combination studies of gemcitabine in combination (with oxaliplatin, and with the targeted therapies bevacizumab and cetuximab) have been negative, though based on strikingly positive Phase II data generated in cancer centers. Several studies suggest that taxanes are active in pancreatic cancer, but a randomized trial of gemcitabine with taxanes has not been preformed, probably on the basis that the differences in Phase II were insufficiently persuasive. The development of a novel taxane conjugate with albumin, abraxane, with established activity in breast cancer, prompted a Phase II trial of gemcitabine/abraxane by Von Hoff (6). Phase I/II data were highly promising, with response rates of the order of 40%, with tolerable toxicity, and a one-year survival of about 48%. A phase III trial of gemcitabine versus gemcitabine/abraxane is in progress, and based on these promising data has served as the control chemotherapy for previous SU2C trials. The development of a more intensive, but toxic regimen (FOLFIRINOX) in no way diminishes the enthusiasm for this chemotherapy backbone, given the activity in Phase II trials that appears comparable (7). Given the promise of this regimen, and the possibility of making a substantial improvement in outcome with additional targeted interventions, we propose to continue to use this regimen in the current study.

Of particular interest in extending these studies to pancreatic cancer is the finding that autophagy inhibition is particularly deleterious to cell lines bearing a mutant Kras protein. Additional studies as part of the SU2C pancreatic cancer project reveal that an autophagy program is activated in the presence of mutant Kras, and thus prompts the testing of this strategy in a setting in which Kras is commonly (about 85%) mutated (SU2C, unpublished data).

Inclusion criteria

• Patients must have histologically or cytologically documented advanced or metastatic adenocarcinoma of the pancreas.
• Patients must have measurable disease as defined by the RECIST criteria as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20mm with conventional techniques on either CT or MRI. Marker (CA19-9 or CEA) elevation alone is insufficient for entry.
• Patients may have had prior adjuvant treatment for pancreatic cancer. The last dose of chemotherapy must have been 4 months prior to study entry.
• Patients with prior radiotherapy are acceptable. It must be at least 4 months since administration of radiation therapy and all signs of toxicity must have abated.
• Patients must be age 18 years or older.
• Patients must have an ECOG performance status of 0-1.
• The following required Initial Laboratory Values should be obtained within 4 weeks of the start of treatment:

• Granulocytes 1,500/ml
• Platelet Count 100,000/ml
• Creatinine 1.5 x upper limit of normal
• Bilirubin 1.5 x upper limit of normal
• AST 5 x upper limit of normal
• Patients must not be pregnant or lactating as chemotherapy is thought to present substantial risk to the fetus/infant.
• Patients must have an accessible primary tumor or metastasis, and be willing to have a pre-treatment and post-treatment tumor biopsy (at 6 to 8 weeks after beginning).
• Patients must have a life expectancy of greater than three months.
• Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Patients may not be receiving any other investigational agents
• Known allergy to HCQ
• Patients with previous treatment with abraxane.
• Patients on therapeutic doses of Coumadin ( 1 mg daily). The use of therapeutic or prophylactic low molecular weight heparin or fragmin is permitted.
• Patients with known G6PD deficiency, severe psoriasis, porphyria, macular degeneration or severe diabetic retinopathy are ineligible because of the potential for greater HCQ toxicity.